1. Field of the Invention
The present invention relates to pathogenic compositions for use in blood and blood products, and blood containers, such as a blood donation bag. The present invention also relates generally to a method of processing and disinfecting human blood products. More particularly, this invention relates to a method of disinfecting whole blood, blood cells, plasma proteins, and plasma so that they may be used safely and effectively for diagnostic, therapeutic or research purposes. The present invention also relates to applications vis the blood circulatory system for controlling the pathological state produced by a pathogen, typically a viral, bacterial, protozoan, fungal or parasitic agent (at any stage of the life-cycle of the parasitic agent).
2. Description of Prior Art
The development of plastic blood collection bags has facilitated the separation of donated whole blood into its various components and analogous products, thereby making these different blood products (e.g., platelet concentrates) available as a transfusion product. With the passage of time and accumulation of research and clinical data, transfusion practices have changed greatly. One aspect of current practice is that whole blood is rarely administered; rather, patients needing red blood cells are given packed red cells, patients needing platelets are given platelet concentrate, and patients needing plasma are given plasma.
However, the increase in transfusing blood products finds a concomitant increase in the transmission of disease to the transfusion recipient. There is an existing and great need to assure a disease-free blood supply.
Blood products from human and animal donors are widely used for therapeutic, diagnostic and experimental purposes. A persistent problem associated with using blood products from human and animal donors is that these products are subject to contamination by blood-borne viruses and other micro-organisms such as bacteria. Of particular threat are viruses that appear to cause various forms of hepatitis, including the hepatitis B virus, the non-A, non-B hepatitis virus or viruses. Others of interest are cytomegalovirus and Epstein-Barr virus.
Viruses linked with the incurable and often fatal disease known as acquired immune deficiency syndrome (AIDS) are caused by a retrovirus or group of retroviruses (HIV, HIV-1, and HIV-2). The most common cause of AIDS is thought to be HIV-1.
The threat of hepatitis, AIDS, and bacterial transmission through transfusion and administration of blood products is not limited to blood cells but extends to the administration of plasma and plasma fractions such as Factor VIII concentrates, Factor IX concentrates, gamma globulin, and anti-thrombin III.
Disinfecting whole blood and blood products, including red blood cells, plasma, and plasma fractions with disinfectants strong enough to significantly inactivate viruses, bacteria and other organisms has generally been discounted because active agents strong enough to inactivate the pathogen typically damage cellular blood constituents or inactivate plasma and plasma protein factions. Additionally, the presence of any residual disinfectant in the blood product to be transfused could be hazardous to the recipient of the transfusion.
A typical component separation procedure used in the United States, the citrate-phosphate-dextrose-adenine (CPDA-1) system, utilizes a series of steps to separate donated blood into three components, each component having substantial therapeutic and monetary value. The procedure typically utilizes a blood collection bag which is integrally attached via flexible tubing to at least one, and preferably two or more, satellite bags. Using centrifugation, whole blood may be separated by differential sedimentation into such valuable blood components as plasma, packed red cells (PRC), platelets suspended in clear plasma (platelet-rich plasma, or PRP), platelet concentrate (PC), and cryoprecipitate (which may require extra processing).
Commonly used systems other than CPDA-1 include Adsol, Nutricell, and SAG-M. In these latter systems, the collection bag contains only anti-coagulant, and the nutrient solution may be pre-placed in a satellite bag. This nutrient solution is transferred into the PRC after the PRP has been separated from the PRC, thereby achieving a higher yield of plasma and longer storage life for the PRC. Improvements in current practices of viral marker screening and donor self-exclusion are continuously increasing the safety of the blood supply. However, despite these practices, a risk of transmission of pathogens with the transfusion of cellular components of blood remains since current screening tests do not screen for rarely occurring or as yet unknown transfusion transmissible pathogens (Dodd, R. Y. New Engl. J. Med. 327:419-421 (1992); Soland, E. M., et al. J. Am. Med. Assoc. 274:1368-1373 (1995); Schreiber, G. B., et al. New Engl. J. Med. 334:1685-1690 (1996)).
To combat the deficiencies associated with screening practices, the use of sterilization procedures of blood, red blood cell concentrates (RBCC), and other blood-derived components hold promise for eliminating pathogen transmission. In this connection, various approaches have been used to sterilize blood cells, the most efficacious so far use photochemical methods (Ben-Hur, E. and B. Horowitz Photochem. Photobiol. 62:383-388 (1995); Ben-Hur, E. and B. Horowitz AIDS 10:1183-1190 (1996)). The most promising photochemical methods employ the use of phthalocyanines (which are activated by light in the far red (660-700 nm)) for sterilization of RBCC (Horowitz, B., et al. Transfusion 31:102-108 (1991); Ben-Hur, E., et al. J. Photochein. Photobiol. B:Biol. 13:145-152 (1992)).
Pasteurization and other physical-chemical techniques have been used to remove or inactivate blood components, but most of these techniques have been limited to fresh plasma or fresh-frozen plasma. To date, these techniques are not suitable for treating cellular components of whole blood.
One disinfectant in use for blood products is beta-propiolactone. Beta-propiolactone, however, is a known carcinogen and hence potentially very dangerous. To the extent that significant residual amounts of this material may remain in the blood product which is actually transfused, the use of propiolactone represents a potential hazard.
There is described in U.S. Pat. No. 4,833,165 (issued on May 23, 1989, in the name of Allan Louderback) the use of as little as 0.1% formaldehyde and/or phenol to inactivate HTLV-III in blood. However, recently available data and information indicate that red blood cells treated with as little as 0.02% formaldehyde and 0.01% phenol are not viable and not suitable for transfusion.
Viral inactivation by stringent sterilization has not found acceptance since this method typically destroys erythrocytes, thrombocytes, and the labile plasma proteins, such as clotting factor VIII. Viable RBC's can be characterized by one or more of the following: capability of synthesizing ATP; cell morphology; P50 values; filterability or deformability; oxyhemoglobin, methemoglobin and hemochrome values; MCV, MCH, and MCHC values; cell enzyme activity; and in vivo survival. Thus, if virally inactivated cells are damaged to the extent that the cells are not capable of metabolizing or synthesizing ATP, or the cell circulation is compromised, then their utility in transfusion medicine is compromised.
Viral inactivation by stringent steam sterilization is not acceptable for the above reasons. Dry heat sterilization, like wet steam, is harmful to blood cells and blood proteins at the levels needed to reduce viral infectivity. Use of stabilizing agents such as carbohydrates does not provide sufficient protection to the delicate blood cells and proteins from the general effects of exposure to high temperature and pressure.
Methods that are currently employed with purified plasma protein fractions, often followed by lyophilization of the protein preparation, include treatment with organic solvents and heat or extraction with detergents to disrupt the lipid coat of membrane enveloped viruses. Lyophilization (freeze-drying) alone has not proven sufficient to inactivate viruses, or to render blood proteins sufficiently stable to the effects of heat sterilization. The organic solvent or detergent method employed with purified blood proteins cannot be used with blood cells as these chemicals destroy the lipid membrane that surrounds the cells.
Another viral inactivation approach for plasma proteins first demonstrated in 1958 has involved the use of a chemical compound, beta-propiolactone, with ultraviolet (UV) irradiation. This method has not found acceptance in the United States due to concern over the toxicity of beta-propiolactone in the amounts used to achieve some demonstrable viral inactivation and also due to unacceptable levels of damage to the proteins caused by the chemical agents. Concern has also been raised over the explosive potential for beta-propiolactone as well. Attempts to inactivate viral decontaminants using photosensitizers and light have also been developed using some non-psoralen photosensitizers. The photosensitizers that have been employed are typically dyes. Examples include dihematoporphyrin ether (DHE), Merocyanine 540 (MC540) and methylene blue.
It would be highly desirable to be provided with anti-pathogenic compositions for use in blood and blood products, and blood containers, such as a blood donation bag.
It would be highly desirable to be provided with a method for processing and disinfecting human blood products.
It would be highly desirable to be provided with a method for disinfecting whole blood, blood cells, plasma proteins, and plasma so that they may be used safely and effectively for diagnostic, therapeutic or research purposes.
It would be highly desirable to be provided with a method vis the blood circulatory system for controlling the pathological state produced by a pathogen, typically a viral, bacterial, protozoan, fungal or parasitic agent.